Project Summary: Understanding the role of chronic stress in the progression of different diseases, including cancer, has become essential to develop personalized treatments that can improve clinical outcomes. Alterations in mental and psychological states, such as chronic stress, depression and anxiety disorders, may accelerate tumor growth and promote resistance to chemotherapeutic treatments. The consequences of these biobehavioral disorders are prominently seen in ovarian cancer patients, since these women report significant levels of psychological distress. These disorders have been associated with sustained activation of the sympathetic nervous system leading to increased catecholamine levels and inflammation in the tumor microenvironment. Pro-inflammatory pathways, such as the NF-kB signaling pathway, have been linked to ovarian cancer growth and progression. As a long-term goal, this proposal aims to investigate the mechanisms by which chronic stress contributes to ovarian cancer progression. To address this goal, we will investigate the role of IkBKe and the NF-kB signaling pathway in adrenergic-induced ovarian cancer progression. Our central hypothesis states that activation of IkBKe by adrenergic signaling promotes ovarian cancer progression. To answer our hypothesis, specific aim 1 will determine if catecholamine-induced IkBKe activity results in phosphorylation of NF-kB effectors and subsequent transcriptional activity in vitro. We will evaluate phosphorylation patterns and transcription of NF-kB target genes to determine if catecholamines induce IkBKe phosphorylation and resulting NF-kB transcriptional activity. Specific aim 2 will focus on determining if catecholamine-induced IkBKe activation mediates pro-tumoral cellular changes in ovarian cancer. Through functional assays, we will examine the effect of IkBKe activation on ovarian cancer cell invasive potential and inflammatory profile. In addition, we will evaluate IkBKe activation and its correlation with advance disease in ovarian cancer patients. Finally, specific aim 3 will study the requirement of IkBKe activation for ovarian cancer tumor progression in two in vivo orthotopic animal stress models. This contribution will be significant because it will have implications in the treatment of ovarian cancer patients. By generating data that provides the underlying mechanism on how chronic stress can induce cancer progression, novel therapeutic agents and psychological interventions could be developed that could improve quality of life and survival rates across the United States and Puerto Rico.